KR20230031322A - Compositions of Compounds that Modulate Cellular Metabolism and Methods of Use - Google Patents

Abstract

A novel class of compounds according to Formula I, Formula II or Formula III, wherein W ₁ to W ₄ , Z ₁ to Z ₄ , Z ₁ to Z ₅ , X, Y, n and R ₁ to R ₈ are as defined in the claims and description of the embodiments), as well as combining compounds of this class with pharmaceutically acceptable diluents or carriers , and pharmaceutical compositions comprising, optionally in further combination with a therapeutically active agent, and the use of these compounds in the medical community and for the manufacture of medicaments in the treatment of diseases acting on FABP4. In an embodiment, ring Z contains Z ₁ -Z ₄ . In other embodiments, ring Z contains Z ₁ -Z ₅ .
[Formula I]

Description

Novel compounds that modulate cellular metabolism and their uses

Cross reference to related fields of application

This application claims priority from US Provisional Patent Application Serial No. 63/045,079, filed on June 27, 2020, the entirety of which is incorporated herein by reference in its entirety.

FIELD OF EMBODIMENT

The present invention relates to novel compounds for the treatment or prevention of diseases associated with metabolism and inflammation, including but not limited to type 2 diabetes, obesity, cardiovascular disease, asthma, cancer and other diseases. The compounds of the invention specifically interact with fatty acid binding protein (FABP) 4 and improve glucose consumption in adipocytes.

FABPs are a family of proteins that reversibly bind free fatty acids and other lipid molecules and facilitate their transport in cells. To date, nine different FABP isoforms have been identified in mammals. FABP isoforms show differential expression patterns in different tissues. Fatty acid binding protein 4 (FABP4), also referred to as aP2 in the literature, is expressed predominantly in adipocytes and macrophages and plays key metabolic and inflammatory pathways in these cells, such as lipid storage and degradation, signaling and eicosanoid production. mediate Moreover, FABP4 is also secreted into plasma and has been proposed to act as an adipose-derived factor regulating systemic glucose homeostasis.

Genetic knockout studies in mice have provided insight into the tissue-specific and systemic functions of FABP4. Importantly, when mice carrying a homozygous deletion of the FABP4 gene were fed a high-fat diet for a long period of time, they gained weight comparable to wild-type and were protected from hyperglycemia and insulin resistance (Hotamisligil et al. , Science. 1996 Nov 22; 274 (5291): 1377-9). In addition, FABP4 deficiency significantly protected apolipoprotein E (ApoE) knockout mice from atherosclerosis, a phenotype attributable to FABP4 modulation of inflammatory pathways in macrophages (Makowski et al. , Nat Med. 2001 June;7(6): 699-705]). FABP4 expression was also detected in airway epithelial cells, and FABP4 deficiency was demonstrated to be protective in a mouse model of allergic lung inflammation (Shum et al. , J Clin Invest. 2006 Aug; 116(8): 2183-2192 ]).

Several reports have been published in the literature linking FABP4 expression levels and functions with a number of pathologies in humans. For example, a reduced risk of type 2 diabetes and coronary heart disease has been observed in individuals carrying a genetic mutation in the promoter region of FABP4 (rs77878271) that results in reduced expression of these genes (Tuncman et al. , Proc Natl Acad Sci US A. 2006 May 2; 103(18): 6970-5]). In addition, the same polymorphism was associated with reduced atherosclerotic disease symptoms in an independent study (Saksi et al. , Circ Cardiovasc Genet. 2014 Oct; 7(5): 588-98). Moreover, triple-negative breast cancer patients with a single nucleotide polymorphism in the 3' untranslated region (UTR) of FABP4 (rs1054135-GG genotype) that also resulted in decreased FAB4 expression were associated with reduced risk of disease progression and long-term disease-free survival time. (Wang et al. , Oncotarget. 2016 Apr 5; 7(14): 18984-98). Increased expression of FABP4 has been observed in preeclamptic placenta and has been suggested to play a role in the pathogenesis of preeclampsia (Yan et al. , Placenta. 2016 Mar; 39: 94-100). . Similarly, granulosa cells from patients with polycystic ovary syndrome show increased expression of FABP4, which has been associated with clinical characterization of the disease (Hu and Qiao, Endocrine. 2011 Oct; 40(2): 196-202). ). Collectively, these studies demonstrated an active role of FAPB4 in regulating systemic metabolism and inflammation, and suggested that pharmacological targeting of FABP4 could be used as a strategy for the treatment of various diseases associated with FABP4 function.

Adipocytes play a central role in systemic glucose homeostasis. One of these major roles is to absorb excess glucose from plasma and store it in the form of lipids. Adipocyte dysfunction due to metabolic stress and inflammation often leads to complications such as hyperglycemia and insulin resistance. Of note, FABP4-deficient mice showed increased deposition of glucose to adipose tissue. Adipocytes isolated from these animals showed a significant increase in the conversion of glucose to fatty acids compared to their wild-type counterparts (Shaughnessy et al. , Diabetes Jun 2000; 49(6): 904-911). . Thus, increasing glucose consumption in adipocytes can be achieved by targeting FABP4.

The literature and certain prior patent applications (e.g. WO 00/47734, WO 00/15229, WO 00/15230, WO 02/40448, WO 01/54694, WO 00/59506 and WO 2004/063156) generally refer to FABP Although various explanations are provided for the concept of inhibition of FABP4, and in particular inhibition of FABP4, no solution(s) such as the present invention are provided for all unmet needs in any discussion in these prior documents. Specifically, the present invention describes a new class of compounds that bind to FABP4 and modulate adipocyte metabolism to promote increased glucose utilization.

The present invention, in one of its embodiments, relates to a compound of Formula I or a pharmaceutically acceptable salt or stereoisomer thereof:

[Formula I]

(In the above formula,

W _1-4 and Z ₁ -Z ₅ are each independently -C, -CH, CH ₂ , O, S or N;

X is independently CH ₂ , N or CHR ₄ ;

Y is independently CH ₂ or CHR ₅ ;

n is a number from 0 to 3;

At least one R ₁ on ring Z is CN, OH, COOH, OCH ₃ , CF ₃ , CONH ₂ , B(OH) ₂ , B(OR) ₂ , acid isostere, substituted amine, ether and independently selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cyclic or heterocyclic substituted or unsubstituted cycloaryl or cycloheteroaryl, wherein the substituted cycloaryl or cycloheteroaryl is hydrogen , CN, OH, COOH, OCH ₃ , CF ₃ , CONH ₂ , B(OH) ₂ , B(OR) ₂ , acid isomers, substituted amines, ethers and halogens, substituted or unsubstituted alkyls, substituted or may be substituted with unsubstituted cyclic or heterocyclic substituted or unsubstituted cycloaryl or cycloheteroaryl, SO ₂ NH ₂ ;

At least one R ₂ on ring (W) is CN, OH, CHF ₂ , CH ₂ F, CF ₃ , COOH, CONH ₂ , B(OH) ₂ , B(OR) ₂ , acid isostere, halogen and bicyclic independently selected from the group consisting of heteroaryl;

R ₇ is hydrogen or CN, COOH, CONH ₂ , B(OH) ₂ , B(OR) ₂ or an acid isostere;

R is alkyl;

R ₃ , R ₄ , R ₅ or R ₈ , or R ₆ when n is not 0,

(1) hydrogen;

(2) an alkyl or ether having 1 to 12 carbon atoms;

(3) a substituted amine, or

(4) --(CH ₂ ) _m G, wherein m is 1 to 12, and G is,

(a) cycloalkyl containing 3 to 6 carbon atoms;

(b) aryl or heteroaryl;

(c) CF ₃ , CF ₂ H or CFH ₂ , or

(d) independently selected from heterocycles;

provided that none of R ₃ , R ₄ , R ₅ , R ₈ or R ₆ are hydrogen.

An object of the present invention is a compound according to formula I, formula II or formula III for use in the treatment of diseases which act on fatty acid binding protein (FABP4).

Another object of the present invention is a pharmaceutical composition for use in the treatment of diseases acting on FABP4, comprising as an active ingredient a compound according to Formula I, Formula II or Formula III in combination with a pharmaceutically acceptable diluent or carrier. am. Here, the pharmaceutical composition may further comprise additional therapeutically active agents.

Another object of the present invention is a method for treating a disease acting on FABP4, wherein the method provides a compound according to formula I, formula II or formula III to a subject (preferably a human) in need of such treatment. (optionally including co-administration of the other therapeutic agent as a single (or multiple) administration, either simultaneously or sequentially) in an effective amount.

Another object of the present invention is a method for inhibiting FABP4, wherein the method administers an effective amount of a compound according to Formula I, Formula II or Formula III to a subject (preferably, a human) in need of such treatment. It includes steps to

Another object of the present invention is the use of a compound according to formula I, formula II or formula III for the manufacture of a medicament for use in the treatment of diseases which act on the fatty acid binding protein FABP4. Examples of such diseases include type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, atherosclerosis, intracranial atherosclerotic disease, nonalcoholic steatohepatitis, asthma, vascular dementia, multiple sclerosis, Alzheimer's disease, and other chronic inflammatory and autoimmune diseases. /Inflammatory diseases, chronic heart disease, polycystic ovarian syndrome, pre-eclampsia and cancer.

Other features and advantages of the present invention will become apparent from the detailed description and claims.

Now, preferred embodiments of the present invention will be described with reference to the drawings. Like elements in the various drawings are identified by like reference numerals.

Now, each embodiment of the present invention will be described in detail. Such embodiments are provided by way of explanation of the present invention, and the present invention is not intended to be limited thereto. In fact, those skilled in the art will recognize that various modifications and changes may be made upon reading this specification and viewing the drawings.

In one embodiment, the invention is a compound of Formula I or a pharmaceutically acceptable salt or stereoisomer thereof:

[Formula I]

(In the above formula,

W _1-4 and Z ₁ to Z ₅ are each independently -C, -CH, CH ₂ , O, S or N;

X is independently CH ₂ , N or CHR ₄ ;

Y is independently CH ₂ or CHR ₅ ;

n is a number from 0 to 3;

At least one R ₁ on ring Z is CN, OH, COOH, OCH ₃ , CF ₃ , CONH ₂ , B(OH) ₂ , B(OR) ₂ , acid isomers, substituted amines, ethers and halogens, substituted or It is independently selected from the group consisting of unsubstituted alkyl, substituted or unsubstituted cyclic or heterocyclic substituted or unsubstituted cycloaryl or cycloheteroaryl, wherein the substituted cycloaryl or cycloheteroaryl is hydrogen, CN, OH , COOH, OCH ₃ , CF ₃ , CONH ₂ , B(OH) ₂ , B(OR) ₂ , acid isomers, substituted amines, ethers and halogens, substituted or unsubstituted alkyls, substituted or unsubstituted cyclics or a heterocyclic substituted or unsubstituted cycloaryl or cycloheteroaryl, SO ₂ NH ₂ ;

At least one R ₂ on ring (W) is CN, OH, CHF ₂ , CH ₂ F, CF ₃ , COOH, CONH ₂ , B(OH) ₂ , B(OR) ₂ , acid isostere, halogen and bicyclic independently selected from the group consisting of heteroaryl;

R ₇ is hydrogen or CN, COOH, CONH ₂ , B(OH) ₂ , B(OR) ₂ or an acid isostere;

R is alkyl;

R ₃ , R ₄ , R ₅ or R ₈ , or R ₆ when n is not 0,

(1) hydrogen;

(2) a substituted or unsubstituted alkyl or ether having 1 to 12 carbon atoms;

(3) a substituted amine, or

(4) --(CH ₂ ) _m G, wherein m is 1 to 12, and G is,

(a) cycloalkyl containing 3 to 6 carbon atoms;

(b) aryl or heteroaryl;

(c) CF ₃ , CF ₂ H or CFH ₂ , or

(d) independently selected from heterocycles;

provided that none of R ₃ , R ₄ , R ₅ , R ₈ or R ₆ are hydrogen.

Also, in the compounds of formula I, when both R ₁ and R ₂ are present, each independently is CN, COOH or CONH ₂ .

Also, in the compound of formula (I), formula (I) includes a plurality of R ₁ and R ₂ .

Further, in the compound of formula (I), R ₃ , R ₄ , R ₅ , R ₈ , or R ₆ when n is not 0 are each independently an alkyl having 4 carbon atoms.

Further, in the compound of formula (I), R ₃ , R ₄ , R ₅ , R ₈ , or R ₆ when n is not 0 are each independently an alkyl having 5 carbon atoms.

Further, in the compound of formula (I), R ₃ , R ₄ , R ₅ , R ₈ , or R ₆ when n is not 0 are each independently an alkyl having 6 carbon atoms.

Also, ring Z of the compound of Formula I may have various sizes (eg, it may be a 5-membered ring, a 6-membered ring, etc.).

In some embodiments, ring Z of a compound of Formula I contains Z ₁ to Z ₄ .

In other embodiments, ring Z of the compound of Formula I contains Z ₁ to Z ₅ .

In an embodiment, one or more R ₁ on ring Z is halogen.

In an embodiment, one or more R ₁ on ring Z is CN.

In an embodiment, one or more R ₁ on Ring Z is CF ₃ .

In an embodiment, one or more R ₂ on ring (W) is halogen.

In an embodiment, one or more R ₁ on ring Z comprises CN and/or halogen.

In an embodiment, one or more R ₁ on ring Z includes CN and/or halogen and one or more R ₂ on ring (W) includes another halogen. In some embodiments, a halogen is the same as another halogen. In other embodiments, the halogen is different from another halogen.

In another embodiment, this invention is a compound of Formula II or a pharmaceutically acceptable salt thereof:

[Formula II]

(In the above formula,

n is 0, 1 or 2;

R ₁ is selected from the group consisting of CN, COOH, CONH ₂ , B(OH) ₂ , B(OR) ₂ , acid isosteres and halogens;

R ₂ is selected from the group consisting of CN, COOH, CONH ₂ , B(OH) ₂ , B(OR) ₂ , acid isosteres, halogens and bicyclic compounds;

R ₇ is hydrogen or CN, COOH, CONH ₂ , B(OH) ₂ , B(OR) ₂ or an acid isostere;

R is alkyl;

R ₃ , R ₄ , R ₅ or R ₈ , or R ₆ when n is not 0,

(1) hydrogen;

(2) alkyl having 1 to 12 carbon atoms, or

(3) --(CH ₂ ) _m G, wherein m is 1 to 12, and G is,

(a) cycloalkyl having 3 to 6 carbon atoms;

(b) aryl or heteroaryl, or

(c) independently selected from CF ₃ , CF ₂ H or CFH ₂ ;

provided that G is not a nitrogen-containing or oxygen-containing group;

provided that none of R ₃ , R ₄ , R ₅ , R ₈ or R ₆ are hydrogen.

Also, in the compound of Formula II, when both R ₁ and R ₂ are present, each is independently CN, COOH or CONH ₂ .

Compounds of Formula II also include a plurality of R ₁ and R ₂ .

Further, in the compound of Formula II, R ₃ , R ₄ , R ₅ , R ₈ , or R ₆ when n is not 0 is each independently an alkyl having 4 carbon atoms.

Further, in the compound of formula (I), R ₃ , R ₄ , R ₅ , R ₈ , or R ₆ when n is not 0 are each independently an alkyl having 5 carbon atoms.

Further, in the compound of formula (I), R ₃ , R ₄ , R ₅ , R ₈ , or R ₆ when n is not 0 are each independently an alkyl having 6 carbon atoms.

In another embodiment, the invention is a compound of Formula III or a pharmaceutically acceptable salt thereof:

[Formula III]

(In the above formula,

n is 0, 1 or 2;

R ₁ and R ₂ are each independently CN, COOH, CONH ₂ , B(OH) ₂ , B(OR) ₂ or an acid isostere;

R is alkyl;

R ₃ is

(1) alkyl having 1 to 12 carbon atoms;

(2) --(CH ₂ ) _m is independently selected from G, where m is 1 to 12, and G is

(a) cycloalkyl containing 3 to 6 carbon atoms; and

(b) independently selected from phenyl;

provided that G is not a nitrogen-containing or oxygen-containing group).

In the compound according to formula III, n is 0 and R ₃ is attached at the h-, i- or j-position.

In the compound according to formula III, n is 1 and R ₃ is attached at the h-, i- or j-position.

In the compound according to formula III, n is 2 and R ₃ is attached at the h-, i- or j-position.

Compounds according to formula III are pure optical isomers.

Compounds according to formula III are (+)-isomers.

Justice

As used herein, the term "acid isomer" includes, but is not limited to, the following groups where R is an alkyl group:

The term "alkyl" refers to a saturated straight or branched chain hydrocarbon group having from 1 to 10 carbon atoms. Representative alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl -3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl -2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like, and longer alkyl groups such as heptyl, octyl, and the like, but are not limited thereto. As used herein, "lower alkyl" means an alkyl having from 1 to 6 carbon atoms.

The term "alkylenyl" refers to a divalent alkyl group.

As used herein, the term "alkoxy" includes -O-(alkyl), where alkyl is defined above.

As used herein, the term "amino" refers to the -NH ₂ group.

“Aryl” means a mono, bicyclic or tricyclic aromatic group wherein all rings of the group are aromatic and all ring atoms are carbon atoms. In bicyclic or tricyclic systems, the individual aromatic rings are fused to each other. Examples of aryl groups include 6-membered and 10-membered aryl. Additional examples of aryl groups include, but are not limited to, phenyl, naphthalene, and anthracene.

As used herein, the term “cyano” refers to a substituent having a carbon atom bonded to a nitrogen atom by a triple bond.

As used herein, the term "deuterium" refers to a stable isotope of hydrogen having one proton and one neutron.

The term "halo" denotes chloro, fluoro, bromo or iodo. In some embodiments, halo is chloro, fluoro or bromo. As used herein, the term “halogen” refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" means an -OH group.

The term "oxo" refers to the group ═O and may be attached to either a carbon atom or a sulfur atom.

The term "N-oxide" refers to the oxidized form of the nitrogen atom.

As used herein, the term “cycloalkyl” refers to a saturated or partially saturated single-cyclic, fused-multicyclic, bridged-multicyclic, or spiro-multicyclic carbocycle having from 3 to 15 carbon ring atoms. refers to A non-limiting category of cycloalkyl groups is a saturated or partially saturated single cyclic carbocycle having 3 to 6 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:

As used herein, "heterocycloalkyl" refers to a single cyclic or fused or bridged, spiro multicyclic ring structure, which is saturated or partially saturated, and contains from 3 to 12 ring atoms selected from carbon atoms. and up to 3 heteroatoms selected from nitrogen, oxygen and sulfur. The ring structure may optionally contain up to two oxo groups on carbon or sulfur ring members or N-oxides. Exemplary heterocycloalkyl entities include, but are not limited to:

As used herein, the term “heteroaryl” refers to a single cyclic or fused multicyclic aromatic heterocycle having 3 to 15 ring atoms selected from carbon, oxygen, nitrogen and sulfur. Suitable heteroaryl groups do not contain a ring system that must be aromatically charged (eg, pyrylium). A suitable 5-membered heteroaryl ring (either as a single cyclic heteroaryl or as part of a multicyclic heteroaryl) has one oxygen, sulfur or nitrogen ring atom, or one nitrogen and one oxygen or sulfur, or two, It has 3 or 4 nitrogen ring atoms. A suitable 6-membered heteroaryl ring (either as a single cyclic heteroaryl or as part of a multicyclic heteroaryl) has 1, 2 or 3 nitrogen ring atoms. Examples of heteroaryl groups include pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, iso Thiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindoleyl , pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl, but is not limited thereto.

The term "bicyclic heteroaryl" refers to a heteroaryl as defined above having two constituent aromatic rings, wherein the two rings are fused together and at least one of the rings is as defined above. It is the same heteroaryl. Bicyclic heteroaryl includes bicyclic heteroaryl groups containing 1, 2, 3 or 4 heteroatom ring atoms selected from O, N or S. In certain embodiments where the heteroatom is N, it may be an N-oxide. Bicyclic heteroaryl also includes 8-, 9- or 10-membered bicyclic heteroaryl groups. Bicyclic heteroaryl also includes 8-, 9- or 10-membered bicyclic heteroaryl groups having 1, 2, 3 or 4 heteroatom ring atoms selected from O, N or S. Illustrative examples of bicyclic heteroaryls include, but are not limited to:

Those skilled in the art will recognize that the types of heteroaryl, cycloalkyl and heterocycloalkyl groups listed and exemplified above are not exhaustive and that additional types within the scope of these defined terms may also be selected.

As used herein, the term “substituted” means that a particular group or moiety bears one or more suitable substituents. As used herein, the term “unsubstituted” means that a particular group does not have substituents. As used herein, the term "optionally substituted" means that a specified group is unsubstituted or substituted with a specified number of substituents. When the term “substituted” is used to describe a structural system, substitution means that any atom on the system occurs at a permissive position.

As used herein, the expression “one or more substituents” refers to from one to the maximum possible number of substitution(s) that can occur at any valence permissive position on the system. In certain embodiments, one or more substituents means 1, 2, 3, 4 or 5 substituents. In another embodiment, one or more substituents means 1, 2 or 3 substituents.

Any atom shown herein to have an unsatisfied valence is presumed to have a sufficient number of hydrogen atoms to satisfy the valence of the atom.

When any variable (eg, alkyl or R ^a ) appears in more than one place in any formula or description provided herein, the definition of that variable in each instance does not concern its definition in all other instances. there is no

As used herein, numerical ranges are intended to include all sequential numbers. For example, a range expressed as "0 to 4" or "0 to 4" includes 0, 1, 2, 3 and 4.

When a multifunctional moiety is present, the point of attachment to the rest of the formula can be at any point on the multifunctional moiety. In some embodiments, attachment points are indicated by lines or hyphens. For example, 'aryloxy-' refers to the moiety where the oxygen atom is the point of attachment to the core molecule, whereas aryl is attached to the oxygen atom.

additional definition

As used herein, “proton nuclear magnetic resonance” or 1H NMR is the application of nuclear magnetic resonance in NMR spectroscopy to the hydrogen ^-1 nuclei in a molecule of a substance to determine its structure.

As used herein, the term "individual" includes mammals and non-mammals. Examples of mammals include any member of the mammalian class, namely humans; non-human primates (eg, chimpanzees and other apes and monkey species); farm animals (eg, cows, horses, sheep, goats, pigs); domestic animals (eg rabbits, dogs and cats); and laboratory animals (including rodents such as rats, mice, and guinea pigs); and the like, but are not limited thereto. Examples of non-mammals include, but are not limited to, birds and fish. In one embodiment of the invention, the mammal is a human.

"Patient" includes both humans and animals.

The term "inhibitor" refers to a molecule, such as a compound, drug, enzyme activator or hormone, which blocks or otherwise interferes with a particular biological activity.

The term “modulator” refers to a molecule, such as a compound of the invention, that increases or decreases or otherwise affects the activity of a given enzyme or protein.

The terms "effective amount" or "therapeutically effective amount" refer to an amount of an agent sufficient to provide a desired biological result. This result may be reduction and/or alleviation of the signs, symptoms, or causes of a disease or medical condition, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound, or composition comprising the compound, required to provide a clinically relevant change in a disease state, symptom, or medical condition. An "effective" amount appropriate for any individual case can be determined by one skilled in the art using routine experimentation. Accordingly, the expression “effective amount” generally refers to an amount of an active substance that has a therapeutically desired effect.

As used herein, the terms "treat" or "treatment" include both "prophylactic" and "curative" treatment. “Prophylactic” treatment means delaying the onset of a disease, symptom of a disease, or medical condition, suppressing possible symptoms, or reducing the risk of developing a disease or condition or the risk of its recurrence. A “curative” treatment includes reducing the severity of, or inhibiting the worsening of, an existing disease, symptom or condition. Thus, treatment can ameliorate or prevent a pre-existing disease symptom from worsening, prevent additional symptoms from occurring, ameliorate or prevent an underlying metabolic cause of a symptom, inhibit a disease or disorder, for example, a disease or disorder. stopping the occurrence of, alleviating a disease or condition, causing regression of a disease or condition, alleviating a condition or condition caused by a condition, or stopping the condition or symptoms of a condition.

Additional chemical explanation

Any formula given herein is intended to represent specific variations or forms, as well as compounds having structures depicted as structural formulas. For example, compounds of any of the formulas given herein may have asymmetric or chiral centers and, therefore, may exist in different stereoisomeric forms. All stereoisomers (including optical isomers, enantiomers and diastereomers) and mixtures thereof of the compounds of the general formula are considered to be within the scope of the formula. In addition, certain structures may exist as geometric isomers (ie, cis and trans isomers), tautomeric or atropisomers. All such isomeric forms and mixtures thereof are contemplated herein as part of the present invention. Thus, any formula given herein is intended to represent a racemic compound, one or more enantiomeric forms, one or more diastereomeric forms, one or more tautomeric or atropisomeric forms, and mixtures thereof.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical/chemical differences by methods well known to those skilled in the art, for example by chromatography and/or fractional crystallization. Enantiomers can be converted into diastereomeric mixtures by reaction with appropriate optically active compounds (eg chiral alcohols or chiral auxiliaries such as Mosher's acid chlorides) or by formation of mixtures of diastereomeric salts. It can be separated by conversion to a sex mixture, separation of the diastereomers, and conversion (eg, hydrolysis or desalting) of the individual diastereomers to the corresponding pure enantiomers. Enantiomers can also be separated using chiral HPLC columns. The chiral center of the compounds of the present invention may be designated as "R" or "S" as defined by the IUPAC 1974 recommendation.

The compounds of the present invention may form pharmaceutically acceptable salts, which are also within the scope of the present invention. "Pharmaceutically acceptable salt" refers to a salt of a free acid or free base of a compound of Formula I, Formula II or Formula III, which is non-toxic, physiologically acceptable, and is compatible with the pharmaceutical composition in which it is formulated. compatible and otherwise suitable for formulation and/or administration to a subject. References to compounds herein are understood to include references to pharmaceutically acceptable salts of such compounds unless otherwise indicated.

Compound salts include acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, if a given compound contains both basic moieties (including but not limited to pyridine or imidazole) and acidic moieties (including but not limited to carboxylic acids), it will be appreciated by those skilled in the art that the compound It will be appreciated that it can exist as a zwitterion ("internal salt"); Such salts are included within the term "salts" as used herein. Salts of a compound of the present invention may be prepared, for example, by reacting the compound with an amount, eg an equivalent amount, of a suitable acid or base in the same medium in which the salt precipitates, or in an aqueous medium, followed by lyophilization. can

Exemplary salts include sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, Tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, genticinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate , glutamate, methanesulfonate (“mesylate”), ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis(2-hydroxy-3-naphtho 8)) salts, but are not limited thereto. Pharmaceutically acceptable salts may involve the inclusion of other molecules such as acetate ions, succinate ions or other counter ions. The counter ion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. Also, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of a pharmaceutically acceptable salt may have multiple counter ions. As such, a pharmaceutically acceptable salt may have one or more charged atoms and/or one or more counter ions.

Exemplary acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide. , lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (as tosylate) also known).

Exemplary basic salts include ammonium salts, alkali metal salts (eg sodium, lithium and potassium salts), alkaline earth metal salts (eg calcium and magnesium salts), organic bases (eg organic amines) (eg, dicyclohexylamine), t-butyl amine, and salts with amino acids (eg, arginine, lysine, etc.). Basic nitrogen-containing groups include lower alkyl halides (eg methyl, ethyl and butyl chloride, bromide and iodide), dialkyl sulfates (eg dimethyl, diethyl and dibutyl sulfate), long chain halides (eg For example, decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (eg benzyl and phenethyl bromides), etc.

Additionally, acids and bases generally considered suitable for forming pharmaceutically useful salts from pharmaceutical compounds are described, for example, in P. Stahl et al. , Camille G. (eds.) Handbook of Pharmaceutical Salts: Properties, Selection and Use. (2002) Zurich: Wiley-VCH]; Literature [S. Berge et al. , J. Pharm. Sci. (1977) 66(1) 1-19]; Literature [P. Gould, Int. J. Pharm. (1986) 33 201-217]; See Anderson et al. , The Practice of Medicinal Chemistry (1996), Academic Press, New York]; and The Orange Book, available from Food & Drug Administration, MD, FDA These disclosures are incorporated herein by reference.

Additionally, any compound described herein may also refer to any unsolvated form, or hydrate, solvate or polymorph of such compound and mixtures thereof, even if such form is not explicitly recited. it is intended to "Solvate" means a physical association of a compound of the present invention with one or more solvent molecules. These physical bonds include varying degrees of ionic and covalent bonds (including hydrogen bonds). In certain cases, a solvate will be capable of isolation, for example when one or more solvent molecules are incorporated within the crystal lattice of a crystalline solid. "Solvate" includes both solution phase and isolateable solvates. Suitable solvates include those formed using pharmaceutically acceptable solvents (eg, water, ethanol, etc.). In some embodiments, the solvent is water and the solvate is a hydrate.

One or more compounds of the present invention may optionally be converted to a solvate. Methods for preparing solvates are generally known. Thus, for example, literature [M. Caira et al. , J. Pharm. Sci. , 93(3), 601-611 (2004) describes the preparation of solvates of antifungal fluconazole from water as well as from ethyl acetate. Similar preparations of solvates, hemi-solvates, hydrates and the like are described by EC van Tonder et al. , AAPS PharmSciTech., 5(1), article 12 (2004)]; and AL Bingham et al. , Chem. Commun., 603-604 (2001). A typical, non-limiting procedure is to dissolve a compound of the present invention in a suitable amount of solvent (organic solvent, water, or mixtures thereof) at a temperature above ambient, cool the solution at a rate sufficient to form crystals, followed by isolating the crystals by standard methods. Analytical techniques such as, for example, infrared spectroscopy show the presence of solvent (or water) in the crystal as a solvate (or hydrate).

The present invention also relates to pharmaceutically acceptable prodrugs of compounds of Formula I, Formula II or Formula III, and methods of treatment using such pharmaceutically acceptable prodrugs. The term "prodrug" refers to a prodrug of Formula I, either through a chemical or physiological process such as solvolysis or enzymatic cleavage after administration to a subject, or when physiological conditions (e.g., physiological pH are reached). , converted to a compound of formula II or formula III) to obtain the compound in vivo. A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically acceptable, and otherwise suitable for formulation and/or administration to a subject. Exemplary procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985].

Examples of prodrugs include pharmaceutically acceptable esters of the compounds of this invention, which are also considered part of this invention. Pharmaceutically acceptable esters of this compound include the following groups: (1) the non-carbonyl moiety of the carboxylic acid portion of the ester group is a straight or branched chain alkyl (eg, acetyl, n-propyl, t -butyl or n-butyl), alkoxyalkyl (eg methoxymethyl), aralkyl (eg benzyl), aryloxyalkyl (eg phenoxymethyl), aryl (eg halogen , phenyl optionally substituted, for example with C _1-4 alkyl, C _1-4 alkoxy or amino), obtained by esterification of a hydroxy group; (2) sulfonate esters such as alkyl- or aralkylsulfonyl (eg methanesulfonyl); (3) amino acid esters (eg, L-valyl or L-isoleucyl); (4) phosphonate esters; and (5) mono-, di- or triphosphate esters. Phosphate esters may be further esterified, for example with C _1-20 alcohols or reactive derivatives thereof or 2,3-di(C _6-24 )acyl glycerols. Further discussion of prodrugs can be found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the ACS Symposium Series and Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. is provided in

For example, when a compound of Formula I, Formula II or Formula III contains a carboxylic acid functional group, the prodrug may be, for example, (C ₁ -C ₈ )alkyl, (C ₂ -C ₁₂ )alkanoyloxy. Methyl, 1-(alkanoyloxy)ethyl with 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl with 5 to 10 carbon atoms, 3 to 6 carbon atoms Alkoxycarbonyloxymethyl having , 1-(alkoxycarbonyloxy)ethyl having 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl with 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl with 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonil, gamma-butyrolacton-4-yl, di-N,N-(C ₁ -C ₂ )alkylamino(C ₂ -C ₃ )alkyl (eg β-dimethylaminoethyl), Carbamoyl-(C ₁ -C ₂ )alkyl, N,N-di(C ₁ -C ₂ )alkylcarbamoyl-(C ₁ -C ₂ )alkyl and piperidino-, pyrrolidino- or esters formed by replacing a hydrogen atom of an acid group with a group such as a poline (C ₂ -C ₃ )alkyl or the like.

Similarly, if a compound of Formula I, Formula II or Formula III contains an alcohol functional group, the prodrug may be, for example, (C ₁ -C ₆ )alkanoyloxymethyl, 1-((C ₁ -C ₆ )alka Noyloxy)ethyl, 1-methyl-1-((C ₁ -C ₆ )alkanoyloxy)ethyl, (C ₁ -C ₆ )alkoxycarbonyloxymethyl, N-(C ₁ -C ₆ )alkoxycarbonyl groups such as aminomethyl, succinoyl, (C ₁ -C ₆ )alkanoyl, α-amino(C ₁ -C ₄ )alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl. It can be formed by replacing the hydrogen atom of an alcohol group, wherein each α-aminoacyl group is a naturally occurring L-amino acid, P(O)(OH) ₂ , -P(O)(O(C ₁ -C ₆ ) alkyl) ₂ or glycosyl (a radical resulting from the removal of a hydroxyl group of a carbohydrate in the hemiacetal form); and the like.

When the compound of Formula I, Formula II or Formula III contains an amine functional group, the prodrug may be, for example, R"-carbonyl, R"O-carbonyl, NR"R'-carbonyl (wherein R" and Each R' is independently (C ₁ -C ₁₀ )alkyl, (C ₃ -C ₇ ) cycloalkyl, benzyl, or R"-carbonyl is natural α-aminoacyl or natural α-aminoacyl), -C (OH)C(O)OY ¹ where Y ¹ is H, (C ₁ -C ₆ )alkyl or benzyl, —C(OY ² )Y ³ where Y ² is (C ₁ -C ₄ ) alkyl, Y ³ is (C ₁ -C ₆ )alkyl, carboxy(C ₁ -C ₆ )alkyl, amino(C ₁ -C ₄ )alkyl or mono-N- or di-N,N-(C ₁ -C ₆ )alkylaminoalkyl), -C(Y ⁴ )Y ⁵ where Y ⁴ is H or methyl and Y ⁵ is mono-N- or di-N,N-(C ₁ -C ₆ ) alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl) and the like) by replacing a hydrogen atom in the amine group.

The invention also relates to pharmaceutically active metabolites of compounds of Formula I, Formula II or Formula III, and the use of such metabolites in the methods of the invention. "Pharmaceutically active metabolite" means a pharmacologically active product of the metabolism of a compound of Formula I, Formula II or Formula III or a salt thereof in the human body. Prodrugs and active metabolites of a compound can be determined using conventional techniques known or available in the art. See, eg, Bertolini et al. , J. Med. Chem . 1997, 40 , 2011-2016]; See Shan et al. , J. Pharm. Sci . 1997, 86 (7) , 765-767]; See Bagshawe, Drug Dev. Res . 1995, 34 , 220-230]; See Bodor, Adv. Drug Res . 1984, 13 , 255-331]; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al. , eds., Harwood Academic Publishers, 1991).

Any formula given herein is also intended to represent unlabeled as well as isotopically-labeled forms of the compound. Isotopically-labeled compounds have structures represented by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples ^of isotopes that can be incorporated into the compounds of the present invention are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, 18 O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, respectively. , isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as ³⁶ Cl and ¹²⁵ I. Such isotopically-labeled compounds may be detected by detection or imaging techniques, including metabolic studies (eg, using ¹⁴ C), kinetic studies (eg, using ² H or ³ H), drug or substrate tissue distribution assays. [eg, positron emission tomography (PET) or single photon emission computed tomography (SPECT)], or for radiation therapy of patients. In particular, ¹⁸ F or ¹¹ C-labeled compounds may be particularly suitable for PET or SPECT studies. Furthermore, substitution with heavier isotopes such as deuterium (ie ² H) may provide certain therapeutic benefits resulting from higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically-labeled compounds of the present invention and their prodrugs are generally prepared by the procedures disclosed in the Schemes or Examples, and by substituting readily available isotopically-labeled reagents for non-isotopically-labeled reagents, followed by the preparations described below. can be produced by

Use of the terms “salt,” “solvate,” “polymorph,” “prodrug,” and the like with respect to the compounds described herein refers to enantiomers, stereoisomers, rotational isomers, tautomers, and atropisomers of the compounds of the present invention. It is intended to apply equally to salts, solvates, polymorphs and prodrug forms of isomers and racemates.

In addition, the present invention,

5-[(3-cyanophenyl)methyl]-2-fluoro-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[ (6-cyanopyridin-2-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(6-carboxylic acid Bamoylpyridin-2-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 6-({4-carboxy-7- Hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indol-5-yl}methyl)pyridine-2-carboxylic acid, 5-[(3-cyano-2-fluorophenyl) Methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(1,3-benzoxazol-6-yl)methyl] -7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(1,3-benzoxazol-5-yl)methyl]-7 -Hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(6-fluoropyridin-2-yl)methyl]-7-hexyl-5H ,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(2-fluoropyridin-4-yl)methyl]-7-hexyl-5H,6H,7H ,8H,9H,10H-Cyclohepta[b]indole-4-carboxylic acid, 7-hexyl-5-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-5H,6H,7H ,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-hexyl-5-{[2-(trifluoromethyl)pyridin-4-yl]methyl}-5H,6H,7H ,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(5-cyanopyridin-3-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H ,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(5-cyanothiophen-2-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclo Hepta[b]indole-4-carboxylic acid, 5-[(4-cyanothiophen-2-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b] Indole-4-carboxylic acid, 5-[(5-cyanofuran-2-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[ b] indole-4-carboxylic acid, 5-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H- Cyclohepta[b]indole-4-carboxylic acid, 5-(3-cyanobenzoyl)-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxyl Acid, 5-[(1,3-benzoxazol-7-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(5-cyanothiophen-3-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-hexyl- 5-[(1H-indol-4-yl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(3-carbamoylphenyl )methyl]-7-propyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(3-carbamoylphenyl)methyl] -5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(3-cyanophenyl)methyl]-5H,6H,7H,8H ,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(pyridin-3-yl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[ b] indole-4-carboxylic acid, 7-butyl-5-[(3-methylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(3-methoxyphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[( 3-chlorophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(3-hydroxyphenyl)methyl]- 5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(2-methoxypyridin-4-yl)methyl]-5H,6H, 7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(4-carbamoylphenyl)methyl]-5H,6H,7H,8H,9H,10H -Cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(2-carbamoylphenyl)methyl]-5H,6H,7H,8H,9 H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(4-methylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole -4-carboxylic acid, 7-butyl-5-[(2-cyanophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7 -Butyl-5-[(2-methylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(2-fluoro Lophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(3-carbamoylphenyl)methyl]-7-pentyl-5H ,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(3-cyanophenyl)methyl]-7-pentyl-5H,6H,7H,8H,9H ,10H-Cyclohepta[b]indole-4-carboxylic acid, 5-[(3-carbamoylphenyl)methyl]-7-(2-phenylethyl)-5H,6H,7H,8H,9H,10H -Cyclohepta[b]indole-4-carboxylic acid, 5-[(3-cyanophenyl)methyl]-7-(2-phenylethyl)-5H,6H,7H,8H,9H,10H-cyclohepta [b] indole-4-carboxylic acid, 5-[(3-carbamoylphenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4- Carboxylic acid, 5-[(3-cyanophenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[( 3-carbamoylphenyl)methyl]-7-octyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(3-cyanophenyl)methyl ]-7-octyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(3-fluorophenyl)methyl]-7-hexyl-5H, 6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-hexyl-5-[(pyridin-3-yl)methyl]-5H,6H,7H,8H,9H, 10H-cyclohepta[b]indole-4-carboxylic acid, 7-hexyl-5-[(3-methylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4 -carboxylic acid, 7-hexyl-5-[(3-methoxyphenyl)methyl]-5H,6H,7H,8H,9H,10H -Cyclohepta[b]indole-4-carboxylic acid, 5-[(3-chlorophenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4 -carboxylic acid, 7-hexyl-5-[(2-methoxypyridin-4-yl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid , 5-[(3-carboxyphenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(4-carba Moylphenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(2-carbamoylphenyl)methyl]-7 -Hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-hexyl-5-[(4-methylphenyl)methyl]-5H,6H,7H,8H ,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(4-cyanophenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[ b] indole-4-carboxylic acid, 5-[(2-cyanophenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxyl acid, 7-hexyl-5-[(2-methylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(2-fluoro Phenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(4-fluorophenyl)methyl]-7-hexyl -5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-2-hexyl-2,3,4, 9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole-8 -carboxylic acid, 9-[(3-carboxyphenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-fluoro Rophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-hexyl-9-[(pyridin-3-yl)methyl]-2 ,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-hexyl-9-[(3-methylphenyl)methyl]-2,3 ,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-hexyl-9-[(3-methoxyphenyl)methyl]-2,3,4,9-tetrahydro-1H-car Bazole-8-carboxylic acid, 9-[(3-chlorophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-hexyl- 9-[(3-hydroxyphenyl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-hexyl-9-[(2-methoxypyridine-4 -yl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carboxyphenyl)methyl]-2-hexyl-2,3,4, 9-Tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(4-carbamoylphenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole- 8-carboxylic acid, 9-[(2-carbamoylphenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-hexyl- 9-[(4-methylphenyl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(4-cyanophenyl)methyl]-2-hexyl- 2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(2-cyanophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro- 1H-carbazole-8-carboxylic acid, 2-hexyl-9-[(2-methylphenyl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9- [(2-fluorophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl] -2-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-2-(2- Phenylethyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-4-(2-phenylethyl)-2 ,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-4-(2-phenylethyl)-2,3,4,9 -Tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-2-propyl-2,3,4,9-tetrahydro-1H-carbazole-8 -Carboxylic acid, 9-[(3-cyanophene Nyl)methyl]-2-propyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-butyl-9-[(3-carbamoylphenyl)methyl]-2 ,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-2-pentyl-2,3,4,9-tetrahydro- 1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-2-pentyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 1-Butyl-9-[(3-carbamoylphenyl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl )methyl]-1-(pentyloxy)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-1-(pentyl Oxy)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 1-butyl-9-[(3-cyanophenyl)methyl]-2,3,4,9- Tetrahydro-1H-carbazole-8-carboxylic acid, 6-butyl-5-[(3-carbamoylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole -4-carboxylic acid, 6-butyl-5-[(3-cyanophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 9 -[(3-carbamoylphenyl)methyl]-1-ethyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl ]-1-ethyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carboxyphenyl)methyl]-1-ethyl-2,3,4, 9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-1-propoxy-2,3,4,9-tetrahydro-1H-carbazole -8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-4-ethyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 4-[ (3-carbamoylphenyl)methyl]-3-ethyl-1H,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 4-[(3-cyanophenyl)methyl]-3 -Ethyl-1H,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 3-butyl-4-[(3-carbamoylphenyl)methyl]-1H,2H,3H,4H- Cyclopenta[b]indole-5 -carboxylic acid, 3-butyl-4-[(3-cyanophenyl)methyl]-1H,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 2-butyl-4-[ (3-carbamoylphenyl)methyl]-1H,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 2-butyl-4-[(3-cyanophenyl)methyl]-1H ,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 5-[(3-carbamoylphenyl)methyl]-10-ethyl-5H,6H,7H,8H,9H,10H- Cyclohepta[b]indole-4-carboxylic acid, 5-[(3-cyanophenyl)methyl]-10-ethyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4 -Carboxylic acid, 5-[(3-carbamoylphenyl)methyl]-10-propyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5- [(3-cyanophenyl)methyl]-10-propyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 9-[(3-carboxyphenyl)methyl ]-4-ethyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-3-ethyl-2,3, 4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 10-butyl-5-[(3-carbamoylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta [b] indole-4-carboxylic acid, 10-butyl-5-[(3-cyanophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carb Boxylic acid, 5-[(3-carbamoylphenyl)methyl]-10-pentyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[( 3-cyanophenyl)methyl]-10-pentyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 4-[(3-carbamoylphenyl)methyl ]-2-pentyl-1H,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 4-[(3-cyanophenyl)methyl]-2-pentyl-1H,2H,3H, 4H-Cyclopenta[b]indole-5-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-2-ethyl-2,3,4,9-tetrahydro-1H-carbazole-8 -carboxylic acid, 9-[(3-carboxyphenyl)methyl]-2-ethyl-2,3,4,9-tetrahydro-1H-carbazole -8-carboxylic acid, 5-[(3-carbamoylphenyl)methyl]-7-ethyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(3-cyanophenyl)methyl]-7-ethyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 9-[(3-cyano Phenyl)methyl]-3-ethyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-4-propyl-2 ,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-3-propyl-2,3,4,9-tetrahydro- 1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-3-propyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 4-Butyl-9-[(3-carbamoylphenyl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 4-butyl-9-[(3- Cyanophenyl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 3-butyl-9-[(3-carbamoylphenyl)methyl]-2,3 ,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 3-butyl-9-[(3-cyanophenyl)methyl]-2,3,4,9-tetrahydro-1H-car Bazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-4-pentyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9- [(3-cyanophenyl)methyl]-4-pentyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl] -3-pentyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-3-pentyl-2,3,4, 9-tetrahydro-1H-carbazole-8-carboxylic acid, 4-[(3-carbamoylphenyl)methyl]-3-propyl-1H,2H,3H,4H-cyclopenta[b]indole-5 -carboxylic acid, 4-[(3-cyanophenyl)methyl]-3-propyl-1H,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 2-({7-butyl -5-[(3-carbamoylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indol-4-yl}formamido)acetic acid, 2-({7- Butyl-5-[(3-cia nophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indol-4-yl}formamido)acetic acid, 7-butyl-5-[(3-carbamoylphenyl) Methyl]-N-(2-hydroxyethyl)-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxamide, 7-butyl-5-[(3-cyano Phenyl)methyl]-N-(2-hydroxyethyl)-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxamide, 7-butyl-5-[(3- Fluorophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid and 7-butyl-5-[(3-carboxyphenyl)methyl]-5H, It may be a compound selected from the group consisting of 6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, or a pharmaceutically acceptable salt or stereoisomer thereof.

Another embodiment is a method for administering a compound of the present invention to a subject in need thereof (eg, a human) by administering a pharmaceutical formulation of the present invention to the subject.

Another embodiment is a method for preparing a pharmaceutical formulation of the present invention by mixing at least one pharmaceutically acceptable compound of the present invention and optionally one or more pharmaceutically acceptable additives or excipients.

For preparing pharmaceutical compositions from the compounds described herein, inert, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may consist of about 5% to about 95% of the active ingredient. Suitable solid carriers are known in the art, such as, for example, magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of preparation for various compositions are described in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.].

Compositions and formulations of the present invention can be administered as sterile compositions and sterile formulations. Sterile pharmaceutical formulations may be prepared according to pharmaceutical grade sterilization standards known to those skilled in the art (e.g., United States Pharmacopeia Chapters 797, 1072, and 1211; California Business & Professions Code 4127.7; 16 California Code of Regulations 1751, 21 Code of Federal Regulations 21, or ex-U.S. counterparts to such regulations).

Liquid form preparations include solutions, suspensions and emulsions. As an example, water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions may be mentioned. Also, liquid formulations may include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be combined with a pharmaceutically acceptable carrier such as an inert compressed gas such as nitrogen.

Solid form preparations intended to be converted immediately prior to use into liquid form preparations for oral or parenteral administration are also included. Such liquid forms include solutions, suspensions and emulsions.

In addition, the compounds of the present invention may be transdermally deliverable. Transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions, and for this purpose may be incorporated into matrix or reservoir type transdermal patches as is conventional in the art.

Compounds of the present invention may also be delivered subcutaneously.

The compounds may be administered orally or intravenously.

The pharmaceutical formulation may be in unit dosage form. In this form, the preparation is subdivided into unit doses of appropriate size containing the active ingredient in an amount suitable, eg, an effective amount, to achieve the desired purpose.

The amount of active compound in a unit dose of the formulation may be from about 1 mg to about 1,000 mg, for example from about 1 mg to about 500 mg, particularly from about 1 mg to about 250 mg, or from about 1 mg to about 25 mg, depending on the particular application. may be altered or adjusted.

The actual dosage employed may vary depending on the requirements of the patient and the severity of the condition being treated.

Determination of the appropriate dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dose may be administered in several divided doses during the day as needed.

The dosage and frequency of administration of the compound of the present invention and/or its pharmaceutically acceptable salt will be adjusted according to the judgment of the attending physician in consideration of factors such as the age, condition and size of the patient as well as the severity of the symptom to be treated. A typical recommended daily dosage regimen for oral administration may range from about 1 mg/day to about 500 mg/day, preferably from 1 mg/day to 200 mg/day in two to four divided doses.

Schemes and Examples

Exemplary and non-limiting chemical entities and methods useful in the preparation of the compounds of this invention will now be described with reference to the illustrative synthetic reaction schemes for their general preparation described below and the specific examples below. Those skilled in the art will recognize that other synthetic routes may be used to synthesize the compounds according to the present invention. Although specific starting materials and reagents are shown and discussed herein, other starting materials and reagents may be readily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the exemplary compounds prepared by the methods described above may be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

One skilled in the art will appreciate that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents can be carried through the reaction scheme with or without appropriate protection to yield the desired products. Alternatively, it may be necessary or desirable to use a suitable group that can be carried through the reaction scheme in place of the ultimately desired substituent and is suitably interchangeable with the desired substituent. Each of the reactions shown in the scheme is preferably carried out at a temperature from about 0° C. up to the reflux temperature of the solvent used. Unless otherwise specified, the variables shown in the schemes below are as defined above with reference to Formula I.

The compounds according to the present invention can be prepared according to procedures well known in the chemical arts, particularly in view of the description contained herein, and to Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g. Volume 3; Liebigs Annalen der Chemie, (9): 1910-16, (1985)]; Helvetica Chimica Acta, 41: 1052-60, (1958); It can be synthesized by a synthetic route involving a procedure similar to that for other heterocycles described in Arzneimittel-Forschung, 40(12): 1328-31, (1990). Starting materials are generally available from commercial sources such as Sigma-Aldrich Chemicals (Milwaukee, Wis., USA) or are readily prepared using methods well known to those skilled in the art (see, e.g., Louis et al., including supplement). F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin. (also available via the Beilstein online database).

Synthetic chemical transformations and protecting group methods (protection and deprotection) useful for the synthesis of the compounds, necessary reagents and intermediates according to the present invention are known in the art and are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989)]; Literature [T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999)]; and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995)] and their subsequent editions. The need for such protection will depend on the nature of the remote functionality and the conditions of the manufacturing method. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art.

Additional reactions that are particularly useful in the preparation of the compounds of this invention include alkylation, reductive amination, oxidation, reduction and hydrolysis reactions. Such transformations are well within the skill of the art.

The compounds according to the present invention may be prepared alone or as a compound library comprising, for example, at least 2 or 5 to 1,000 compounds or 10 to 100 compounds. Libraries of compounds of formula I, formula II or formula III can be prepared by a combinatorial "split and mix" approach, or by multiple parallel synthesis using solution phase or solid phase chemistry, or known to those skilled in the art. It can be manufactured by a procedure in which Accordingly, according to a further aspect of the present invention there is provided a compound library comprising at least two compounds of Formula I, Formula II or Formula III, or pharmaceutically acceptable salts thereof.

In the process for preparing the compounds according to the invention, it may be advantageous to separate the reaction products from one another and/or to separate them from starting materials. The desired product of each step or series of steps is isolated and/or purified to the desired degree of homogeneity by techniques commonly used in the art. Typically, such separation involves multi-phase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation or chromatography. Chromatography may include, for example, reverse phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analysis; It may involve any of a number of methods, including simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as small scale thin layer and flash chromatography techniques.

Another class of separation methods involves treatment of the mixture with reagents selected to bind to or separate the desired product, unreacted starting materials, reaction by-products, and the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, and the like. Alternatively, the reagent may be an acid in the case of a basic substance, a base in the case of an acidic substance, a binding reagent such as an antibody, a binding protein, a selective chelating agent such as a crown ether, a liquid/liquid ion extraction reagent (LIX), and the like. The choice of an appropriate separation method depends on the nature of the substances involved, e.g. boiling point and molecular weight during distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of the substance in acidic and basic media during multiphase extraction, etc. .

Single stereoisomers (e.g., enantiomers that are substantially free of their stereoisomers) can be obtained by resolving racemic mixtures using methods such as diastereomer formation with optically active resolving agents (see Eliel , E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994;Lochmuller, C. H., (1975) J. Chromatogr., 113(3): 283- 302]). Racemic mixtures of the chiral compounds of the present invention can be separated and isolated by any suitable method, in which case (1) formation of ionic diastereomeric salts using the chiral compounds and separation by fractional crystallization or other methods. , (2) formation of diastereomeric compounds using chiral derivatization reagents, separation of diastereomers and conversion to pure stereoisomers, and (3) separation of substantially pure or enriched stereoisomers directly under chiral conditions. (See "Drug Stereochemistry, Analytical Methods and Pharmacology," Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993)).

Under method (1), diastereomeric salts are enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl-β- It can be formed by reacting phenylethylamine (amphetamine) and the like with asymmetric compounds having acidic functional groups such as carboxylic acids and sulfonic acids. Diastereomeric salts can be brought to separation by fractional crystallization or ion chromatography. For the separation of optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid, can result in the formation of diastereomeric salts.

Alternatively, in method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p. 322]). Diastereomeric compounds can be formed by reacting an asymmetric compound with an enantiomerically pure chiral derivatizing reagent, such as a menthyl derivative, followed by separation of the diastereomers and hydrolysis to obtain the pure or enriched enantiomers. can Methods for measuring optical purity include preparation of chiral esters such as menthyl esters, for example (-) menthyl chloroformate, in the presence of a base, or Mosher esters of racemic mixtures, i.e., α-methoxy-α-(trifluoro). preparing romethyl)phenyl acetate, and analyzing the 1H NMR spectrum for the presence of two atropisomeric enantiomers or diastereomers (Jacob III. J. Org. Chem. 1982) 47: 4165]). Stable diastereomers of atropisomeric compounds can be separated and isolated by methods for separating atropisomeric naphthyl-isoquinolines followed by normal and reverse phase chromatography (WO 96/15111). By method (3), a racemic mixture of the two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513: 375-378]). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules from asymmetric carbon atoms, such as optical rotation and circular dichroism.

Detailed description of the experiment

Synthesis method A :

Indole intermediates were obtained by Fisher indole synthesis with beta-substituted cyclic ketones and 2-carboxylate-phenyl hydrazine, followed by esterification. Alkylation of the indole nitrogen with the required alkyl bromide and subsequent hydrolysis gave the desired product after purification.

Representative Example: 7-Butyl-5-[(3-carbamoylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid

Step 1.1 : Hydrazine (1.12 g) and ketone (3 g) were mixed in AcOH, stirred at 130° C., after 3 hours the AcOH was distilled off. The reaction was then neutralized with saturated sodium bicarbonate and extracted with EtOAc (300 mL x 3), which was dried and concentrated by rotary evaporation. Purification using column chromatography (30% EtOAc:petroleum ether) gave 1 g of the desired indole product.

Step 1.2 : 1 g of indole was dissolved in 15 ml of MeOH. 1 mL of H ₂ SO ₄ was added and heated at 80 °C. After 16 hours, MeOH was distilled off from the reaction mixture, neutralized with saturated sodium bicarbonate and extracted with EtOAc (300 mL x 3), which was dried and concentrated by rotary evaporation. Purification using column chromatography (20% EtOAc:petroleum ether) gave 900 mg of the desired indole ester product.

Step 2.1 : Indole ester (900 mg) and 3-cyano-benzyl bromide (1.18 g) were dissolved in DMSO (10 mL), then KOH (842 mg) was added at room temperature and stirred. After 2 hours, the reaction was diluted with water and extracted with EtOAc (300 mL x 3), which was dried and concentrated by rotary evaporation. Purification using column chromatography (15% EtOAc:petroleum ether) gave 700 mg of the desired indole ester product.

Step 2.2 : Benzyl indole was dissolved in EtOH:H ₂ O (30:6 mL), then KOH (473 mg) was added at room temperature and heated to 70 °C. After 15 min, the reaction was cooled to room temperature, neutralized with 1 N HCl solution, and extracted with EtOAc (300 mL x 3). The combined organic extracts were then dried and concentrated by rotary evaporation. Purification using MS guided tablets yielded 110 mg of 7-butyl-5-[(3-cyanophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4- carboxylic acid and 105 mg of 7-butyl-5-[(3-carbamoylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid got it

Synthesis method B : Fischer indole synthesis using an unsubstituted cyclic ketone and 2-carboxylate-phenyl hydrazine, followed by esterification to obtain an indole intermediate. A TFAA-DMSO alkylation protocol with the required nucleophile (Masanori Tayu et al. , Org. Biomol. Chem. (2013) 11 496) followed by ester hydrolysis gave the desired product after purification.

Representative Example: 9-[(3-carbamoylphenyl)methyl]-2-pentyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid

Step 1.1 : Hydrazine (6.0 g) and ketone (6.2 g) were mixed in AcOH (100 mL), stirred at 130° C., after 3 hours AcOH was distilled off. The reaction was then neutralized with saturated sodium bicarbonate and extracted with EtOAc (300 mL x 3), which was dried and concentrated by rotary evaporation. Purification using column chromatography (30% EtOAc:petroleum ether) gave 5 g of the desired indole product.

Step 1.2 : 5 g of indole was dissolved in 100 ml of MeOH. 7 mL of conc. H ₂ SO ₄ was added and heated at 80 °C. After 16 hours, MeOH was distilled off from the reaction mixture, neutralized with saturated sodium bicarbonate and extracted with EtOAc (300 mL x 3), which was dried and concentrated by rotary evaporation. Purification using column chromatography (20% EtOAc:petroleum ether) gave 4.2 g of the desired indole ester product.

Step 2 : The indole ester (3 g) was dissolved in DMSO (50 mL), then KOH (3.675 g) was added at room temperature. 3-Cyano-benzyl bromide (5.13 g) was then added in portions and stirred. After 2 hours, the reaction solution was slowly poured into 1 N HCl in a flask equipped with an ice-water bath, and the organic matter was extracted with EtOAc (300 ml x 3), which was dried and concentrated by rotary evaporation. Purification using column chromatography (20% EtOAc:petroleum ether) gave 3.5 g of the desired indole ester product.

Step 3 : To a solution of the indole ester (500 mg) in dichloromethane (7 mL) at -40 °C was added DMSO (0.315 mL). Trifluoro-acetic anhydride (0.617 mL) was added dropwise to this mixture and stirred at -40 °C. After 1 hour, ethyl magnesium bromide (17.647 mL, 1 M) was added dropwise to this mixture. After 2 hours, the reaction solution was slowly poured into a solution of 10 ml of saturated NaHCO ₃ + 20 ml of H ₂ O + 30 ml of EtOAc. The organic layer was separated, dried and concentrated in vacuo. Purification using column chromatography (20% EtOAc:petroleum ether) gave 300 mg of the desired product.

Step 4 : Benzyl indole (150 mg) was dissolved in EtOH:H ₂ O (5:2 mL), then KOH (156 mg) was added at room temperature and stirred. After 16 hours, the reaction solution was neutralized with 1 N HCl solution, and 9-[(3-carbamoylphenyl)methyl]-2-pentyl-2,3,4,9-tetrahydro-1H-carbazole-8 - The solid was filtered as carboxylic acid (30 mg).

The above technical results are reflected in Table 1 below:

Representative HPLC methods that can be used include:

Method A

Column: Kinetex EVO C18 (50 mm x 4.6 mm; 5 μm)

Mobile phase: B1: 0.1% FA in water, A1: 0.1% FA in acetonitrile

Gradient: Time (min)/A1 (%): 0/2, 0.4/2, 2.7/98, 3.40/98, 3.41/2, 3.5/2

Column flow: 2.0 mL/min

Column temperature: 45°C

Method B

Column: ACQUITY UPLC BEH C18 (50 mm x 2.1 mm; 1.7 μm)

Mobile phase: B1: 0.1% FA in water, A1: 0.1% FA in acetonitrile

Gradient: Time (min)/A1 (%): 0/2, 0.4/2, 2.8/98, 3.4/98, 3.41/2, 3.5/2

Column flow: 0.6 ml/min

Column temperature: 60°C

Method C

Column: ACQUITY UPLC BEH C18 (50 mm x 2.1 mm; 1.7 μm)

Mobile phase: B1: 0.1% FA in water, A1: 0.1% FA in acetonitrile

Gradient: Time (min)/A1 (%): 0/2, 0.3/2, 2.3/98, 2.8/98, 2.81/2, 3.0/2

Column flow: 0.8 ml/min

Column temperature: 60°C

Method D

Column: X-BRIDGE C18 (4.6 mm x 150 mm) 5 μm

Mobile phase: A: 10 mM ammonium acetate (aqs), B: acetonitrile

Gradient time: B (%): Diluent 0/10, 1/10, 12/95, 15/98, 20/98, 20.01/10

Column Temperature: Ambient Temperature

Flow rate: 1 mL/min (ACN:water)

Method E

Column: ACQUITY UPLC BEH C18 (50 mm x 2.1 mm; 1.7 μm)

Mobile phase: B1: 0.1% FA in water, A1: 0.1% FA in ACNACN:

Gradient: Time (min)/A1 (%): 0/2, 0.2/2, 5.0/98, 5.8/98, 5.81/2.0, 6.00/2.0

Column flow: 0.8 ml/min

Column temperature: 60°C

Method F

Mobile phase A: 0.1% FA in water

Mobile phase B: 0.1% FA in acetonitrile

Gradient (%) of B: 0/5, 0.3/5, 1.5/60, 2/98, 4/98, 5/5

Flow: 0.6 ml/min

Column: BEH C18, 2.1 mm x 50 mm, 1.7 μm.

Table 2 below shows the correlation with the HPLC method used under the IUPAC nomenclature:

The activity of the compounds on adipocyte glucose consumption was examined in differentiated 3T3-L1 mouse adipocytes. 3T3-L1 preadipocytes (ATCC) were cultured in a growth medium composed of DMEM high glucose (Sigma), 10% FBS (Gibco), 10 U/ml penicillin and 10 μg/ml streptomycin (P/S; Gibco). cultured normally. To induce adipogenic differentiation, a confluent layer of 3T3-L1 cells was grown containing 2 μM rosiglitazone, 1 μM dexamethasone, 500 μM IBMX and 1 μg/ml insulin (Sigma). medium was incubated. After forty-eight (48) hours (day 2), and on days 4 and 6, the medium of the cells was replaced with fresh medium containing 1 μg/ml insulin. On days 8 and 10, medium was supplemented with normal growth medium and insulin addition was omitted. On day 11 or 12, the medium of the cells was replaced with fresh medium containing the indicated compound (10 μM) or the vehicle in which the compound was dissolved (DMSO). The final concentration of DMSO was 0.1% (v/v). Growth medium containing 0.1% DMSO was incubated in culture wells that did not contain cells and was used as a control. After 22-24 hours, the medium was harvested and centrifuged at 10,000 g for 5 minutes. Glucose concentration in the supernatant was measured using a colorimetric assay (Glucose Assay Kit I, Eton Biosciences). Glucose consumption in compound-treated and vehicle-treated cells was measured as loss of glucose from culture medium and was expressed as mean fold change (compound/DMSO) ± standard deviation (SD).

A terbium (Tb) based time resolved fluorescence energy transfer (TR-FRET) assay was used to profile the activity of compounds with FABP4. In the assay, fluorescent fatty acid BODIPY FL from His6-tagged human recombinant FABP4 (His6-FABP4; Cayman Chemicals; catalog number: 10009549) was recorded by recording the energy transfer from the TB donor molecule to the acceptor BODIPY moiety on an anti-His6-tag antibody. Compound-mediated displacement of C12 (Thermo Fisher; catalog number: D3822) is measured. Briefly, compounds were prepared at concentrations of 0.362 mM and 0.0362 mM in DMSO, and BODIPY FL C12 was prepared at 4.2 μM. 1.2 μl of each compound or DMSO (vehicle control) and 1.2 μl of BODIPY FL C12 were added into wells of a 384-well black polypropylene plate. His6-FABP4 and Tb anti-His6 antibodies were administered at concentrations of 83 nM and 49.6 nM, respectively, in assay buffer (25 mM Tris/HCl, pH 7.4, 0.4 mg/mL of γ-globulin, 0.010% NP-40, 1 mM DTT). was made with The protein and antibody solutions were then mixed in a ratio of 34:7 (v/v) and incubated on ice for 30 minutes. The assay was initiated by adding 41 μl of the resulting protein/antibody solution to wells containing compound and BODIPY FL C12. Plates were centrifuged and incubated for 10 minutes at room temperature. TR-FRET signals were recorded using an EnVision Multilabel plate reader (PerkinElmer; TB excitation: 320 nm, BODIPY FL C12 emission: 520 nm; TB emission: 615 nm). Relative fluorescence ratios (520 nm * 10,000/615 nm) were used to calculate compound-mediated inhibition of BODIPY C12 FL fatty acid binding to FABP4. Compounds were tested in triplicate and results were expressed as mean percent inhibition (compound * 100/DMSO) ± standard deviation (SD). Glucose consumption and FABP4 inhibition are shown in Table 3 below.

Although the invention has been described to a particular degree of detail, it is disclosed for purposes of illustration only, and various changes may be made in the details of construction and arrangement of parts without departing from the spirit and scope of the invention. should be understood as

Claims (46)

A compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof:
[Formula I]

(In the above formula,
W _1-4 and Z ₁ -Z ₅ are each independently -C, -CH, CH ₂ , O, S or N;
X is independently CH ₂ , N or CHR ₄ ;
Y is independently CH ₂ or CHR ₅ ;
n is a number from 0 to 3;
At least one R ₁ on ring Z is CN, OH, COOH, OCH ₃ , CF ₃ , CONH ₂ , B(OH) ₂ , B(OR) ₂ , acid isostere, substituted amine, ether and It is independently selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cyclic or heterocyclic substituted or unsubstituted cycloaryl or cycloheteroaryl, wherein the substituted cycloaryl or cycloheteroaryl is Hydrogen, CN, OH, COOH, OCH ₃ , CF ₃ , CONH ₂ , B(OH) ₂ , B(OR) ₂ , acid isomers, substituted amines, ethers and halogens, substituted or unsubstituted alkyls, substituted or unsubstituted cyclic or heterocyclic substituted or unsubstituted cycloaryl or cycloheteroaryl and SO ₂ NH ₂ ;
At least one R ₂ on ring (W) is CN, OH, CHF ₂ , CH ₂ F, CF ₃ , COOH, CONH ₂ , B(OH) ₂ , B(OR) ₂ , acid isostere, halogen and bicyclic independently selected from the group consisting of heteroaryl;
R ₇ is hydrogen or CN, COOH, CONH ₂ , B(OH) ₂ , B(OR) ₂ or an acid isostere;
R is alkyl;
R ₃ , R ₄ , R ₅ or R ₈ , or R ₆ when n is not 0,
(1) hydrogen;
(2) a substituted or unsubstituted alkyl or ether having 1 to 12 carbon atoms;
(3) a substituted amine, or
(4) --(CH ₂ ) _m G, wherein m is 1 to 12, and G is,
(a) cycloalkyl containing 3 to 6 carbon atoms;
(b) aryl or heteroaryl;
(c) CF ₃ , CF ₂ H or CFH ₂ , or
(d) independently selected from heterocycles;
provided that none of R ₃ , R ₄ , R ₅ , R ₈ or R ₆ are hydrogen. The compound according to claim 1, wherein both R ₁ and R ₂ are present, and each is independently CN, COOH or CONH ₂ . 2. The compound according to claim 1, wherein Formula I comprises a plurality of R ₁ and R ₂ . The compound according to claim 1, wherein R ₃ , R ₄ , R ₅ , R ₈ , or R ₆ when n is not 0 are each independently an alkyl having 4 carbon atoms. The compound according to claim 1, wherein R ₃ , R ₄ , R ₅ , R ₈ , or R ₆ when n is not 0 are each independently an alkyl having 5 carbon atoms. The compound according to claim 1, wherein R ₃ , R ₄ , R ₅ , R ₈ , or R ₆ when n is not 0 are each independently an alkyl having 6 carbon atoms. The compound according to claim 1, wherein the ring Z contains Z ₁ to Z ₄ . The compound according to claim 1, wherein the ring Z contains Z ₁ to Z ₅ . The compound according to claim 1, wherein at least one R ₁ on ring Z is halogen. The compound according to claim 1, wherein at least one R ₁ on ring Z is CN. The compound according to claim 1, wherein at least one R ₁ on ring Z is CF ₃ . The compound according to claim 1, wherein at least one R ₂ on the ring (W) is halogen. The compound according to claim 1, wherein at least one R ₁ on ring Z comprises the CN and/or halogen. The compound according to claim 1, wherein at least one R ₁ on ring Z includes CN and/or halogen, and at least one R ₂ on ring (W) includes another halogen. 15. The compound according to claim 14, wherein the halogen is the same as another halogen. 15. The compound of claim 14, wherein the halogen is different from the other halogen. A compound of Formula II or a pharmaceutically acceptable salt thereof:

[Formula II]

(In the above formula,
n is 0, 1 or 2;
R ₁ is selected from the group consisting of CN, COOH, CONH ₂ , B(OH) ₂ , B(OR) ₂ , acid isosteres and halogens;
R ₂ is selected from the group consisting of CN, COOH, CONH ₂ , B(OH) ₂ , B(OR) ₂ , acid isosteres, halogens and bicyclic compounds;
R ₇ is hydrogen or CN, COOH, CONH ₂ , B(OH) ₂ , B(OR) ₂ or an acid isostere;
R is alkyl;
R ₃ , R ₄ , R ₅ or R ₈ , or R ₆ when n is not 0,
(1) hydrogen;
(2) alkyl having 1 to 12 carbon atoms, or
(3) --(CH ₂ ) _m G, wherein m is 1 to 12, and G is,
(a) cycloalkyl containing 3 to 6 carbon atoms;
(b) aryl or heteroaryl, or
(c) independently selected from CF ₃ , CF ₂ H or CFH ₂ ;
provided that G is not a nitrogen-containing or oxygen-containing group;
provided that none of R ₃ , R ₄ , R ₅ , R ₈ or R ₆ are hydrogen. 18. The compound according to claim 17, wherein R ₁ and R ₂ are both present, and each is independently CN, COOH or CONH ₂ . 18. The compound of claim 17, wherein Formula II contains a plurality of R ₁ and R ₂ . The compound according to claim 17, wherein R ₃ , R ₄ , R ₅ , R ₈ , or R ₆ when n is not 0 is each independently an alkyl having 4 carbon atoms. The compound according to claim 17, wherein R ₃ , R ₄ , R ₅ , R ₈ , or R ₆ when n is not 0 are each independently an alkyl having 5 carbon atoms. The compound according to claim 17, wherein R ₃ , R ₄ , R ₅ , R ₈ , or R ₆ when n is not 0 are each independently an alkyl having 6 carbon atoms. A compound of Formula III or a pharmaceutically acceptable salt thereof:
[Formula III]

(In the above formula,
n is 0, 1 or 2;
R ₁ and R ₂ are each independently CN, COOH or CONH ₂ ;
R ₃ is
(1) alkyl having 1 to 12 carbon atoms;
(2) --(CH ₂ ) _m is independently selected from G, where m is 1 to 12, and G is
(a) cycloalkyl containing 3 to 6 carbon atoms;
(b) independently selected from phenyl;
provided that G is not a nitrogen-containing or oxygen-containing group). 24. The compound of claim 23, wherein n is 0 and R ₃ is attached at the h-, i- or j-position. 24. The compound of claim 23, wherein n is 1 and R ₃ is attached at the h-, i- or j-position. 24. The compound of claim 23, wherein n is 2 and R ₃ is attached at the h-, i- or j-position. 24. A compound according to any one of claims 1, 17 and 23, which is a pure optical isomer. 24. The compound according to claim 23, which is the (+)-isomer. 24. The compound according to claim 23, which is the (-)-isomer. 5-[(3-cyanophenyl)methyl]-2-fluoro-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[ (6-cyanopyridin-2-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(6-carboxylic acid Bamoylpyridin-2-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 6-({4-carboxy-7- Hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indol-5-yl}methyl)pyridine-2-carboxylic acid, 5-[(3-cyano-2-fluorophenyl) Methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(1,3-benzoxazol-6-yl)methyl] -7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(1,3-benzoxazol-5-yl)methyl]-7 -Hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(6-fluoropyridin-2-yl)methyl]-7-hexyl-5H ,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(2-fluoropyridin-4-yl)methyl]-7-hexyl-5H,6H,7H ,8H,9H,10H-Cyclohepta[b]indole-4-carboxylic acid, 7-hexyl-5-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-5H,6H,7H ,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-hexyl-5-{[2-(trifluoromethyl)pyridin-4-yl]methyl}-5H,6H,7H ,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(5-cyanopyridin-3-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H ,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(5-cyanothiophen-2-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclo Hepta[b]indole-4-carboxylic acid, 5-[(4-cyanothiophen-2-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b] Indole-4-carboxylic acid, 5-[(5-cyanofuran-2-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[ b] indole-4-carboxylic acid, 5-[(3,5-dimethyl-1,2-oxazol-4-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H- Cyclohepta[b]indole-4-carboxylic acid, 5-(3-cyanobenzoyl)-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxyl Acid, 5-[(1,3-benzoxazol-7-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(5-cyanothiophen-3-yl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-hexyl- 5-[(1H-indol-4-yl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(3-carbamoylphenyl )methyl]-7-propyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(3-carbamoylphenyl)methyl] -5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(3-cyanophenyl)methyl]-5H,6H,7H,8H ,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(pyridin-3-yl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[ b] indole-4-carboxylic acid, 7-butyl-5-[(3-methylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(3-methoxyphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[( 3-chlorophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(3-hydroxyphenyl)methyl]- 5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(2-methoxypyridin-4-yl)methyl]-5H,6H, 7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(4-carbamoylphenyl)methyl]-5H,6H,7H,8H,9H,10H -Cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(2-carbamoylphenyl)methyl]-5H,6H,7H,8H,9 H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(4-methylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole -4-carboxylic acid, 7-butyl-5-[(2-cyanophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7 -Butyl-5-[(2-methylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-butyl-5-[(2-fluoro Lophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(3-carbamoylphenyl)methyl]-7-pentyl-5H ,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(3-cyanophenyl)methyl]-7-pentyl-5H,6H,7H,8H,9H ,10H-Cyclohepta[b]indole-4-carboxylic acid, 5-[(3-carbamoylphenyl)methyl]-7-(2-phenylethyl)-5H,6H,7H,8H,9H,10H -Cyclohepta[b]indole-4-carboxylic acid, 5-[(3-cyanophenyl)methyl]-7-(2-phenylethyl)-5H,6H,7H,8H,9H,10H-cyclohepta [b] indole-4-carboxylic acid, 5-[(3-carbamoylphenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4- Carboxylic acid, 5-[(3-cyanophenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[( 3-carbamoylphenyl)methyl]-7-octyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(3-cyanophenyl)methyl ]-7-octyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(3-fluorophenyl)methyl]-7-hexyl-5H, 6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-hexyl-5-[(pyridin-3-yl)methyl]-5H,6H,7H,8H,9H, 10H-cyclohepta[b]indole-4-carboxylic acid, 7-hexyl-5-[(3-methylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4 -carboxylic acid, 7-hexyl-5-[(3-methoxyphenyl)methyl]-5H,6H,7H,8H,9H,10H -Cyclohepta[b]indole-4-carboxylic acid, 5-[(3-chlorophenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4 -carboxylic acid, 7-hexyl-5-[(2-methoxypyridin-4-yl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid , 5-[(3-carboxyphenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(4-carba Moylphenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(2-carbamoylphenyl)methyl]-7 -Hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 7-hexyl-5-[(4-methylphenyl)methyl]-5H,6H,7H,8H ,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(4-cyanophenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[ b] indole-4-carboxylic acid, 5-[(2-cyanophenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxyl acid, 7-hexyl-5-[(2-methylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(2-fluoro Phenyl)methyl]-7-hexyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(4-fluorophenyl)methyl]-7-hexyl -5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-2-hexyl-2,3,4, 9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole-8 -carboxylic acid, 9-[(3-carboxyphenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-fluoro Rophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-hexyl-9-[(pyridin-3-yl)methyl]-2 ,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-hexyl-9-[(3-methylphenyl)methyl]-2,3 ,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-hexyl-9-[(3-methoxyphenyl)methyl]-2,3,4,9-tetrahydro-1H-car Bazole-8-carboxylic acid, 9-[(3-chlorophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-hexyl- 9-[(3-hydroxyphenyl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-hexyl-9-[(2-methoxypyridine-4 -yl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carboxyphenyl)methyl]-2-hexyl-2,3,4, 9-Tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(4-carbamoylphenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole- 8-carboxylic acid, 9-[(2-carbamoylphenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-hexyl- 9-[(4-methylphenyl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(4-cyanophenyl)methyl]-2-hexyl- 2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(2-cyanophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro- 1H-carbazole-8-carboxylic acid, 2-hexyl-9-[(2-methylphenyl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9- [(2-fluorophenyl)methyl]-2-hexyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl] -2-(2-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-2-(2- Phenylethyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-4-(2-phenylethyl)-2 ,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-4-(2-phenylethyl)-2,3,4,9 -Tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-2-propyl-2,3,4,9-tetrahydro-1H-carbazole-8 -Carboxylic acid, 9-[(3-cyanophene Nyl)methyl]-2-propyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 2-butyl-9-[(3-carbamoylphenyl)methyl]-2 ,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-2-pentyl-2,3,4,9-tetrahydro- 1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-2-pentyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 1-Butyl-9-[(3-carbamoylphenyl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl )methyl]-1-(pentyloxy)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-1-(pentyl Oxy)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 1-butyl-9-[(3-cyanophenyl)methyl]-2,3,4,9- Tetrahydro-1H-carbazole-8-carboxylic acid, 6-butyl-5-[(3-carbamoylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole -4-carboxylic acid, 6-butyl-5-[(3-cyanophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 9 -[(3-carbamoylphenyl)methyl]-1-ethyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl ]-1-ethyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carboxyphenyl)methyl]-1-ethyl-2,3,4, 9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-1-propoxy-2,3,4,9-tetrahydro-1H-carbazole -8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-4-ethyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 4-[ (3-carbamoylphenyl)methyl]-3-ethyl-1H,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 4-[(3-cyanophenyl)methyl]-3 -Ethyl-1H,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 3-butyl-4-[(3-carbamoylphenyl)methyl]-1H,2H,3H,4H- Cyclopenta[b]indole-5 -carboxylic acid, 3-butyl-4-[(3-cyanophenyl)methyl]-1H,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 2-butyl-4-[ (3-carbamoylphenyl)methyl]-1H,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 2-butyl-4-[(3-cyanophenyl)methyl]-1H ,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 5-[(3-carbamoylphenyl)methyl]-10-ethyl-5H,6H,7H,8H,9H,10H- Cyclohepta[b]indole-4-carboxylic acid, 5-[(3-cyanophenyl)methyl]-10-ethyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4 -Carboxylic acid, 5-[(3-carbamoylphenyl)methyl]-10-propyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5- [(3-cyanophenyl)methyl]-10-propyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 9-[(3-carboxyphenyl)methyl ]-4-ethyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-3-ethyl-2,3, 4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 10-butyl-5-[(3-carbamoylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta [b] indole-4-carboxylic acid, 10-butyl-5-[(3-cyanophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carb Boxylic acid, 5-[(3-carbamoylphenyl)methyl]-10-pentyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[( 3-cyanophenyl)methyl]-10-pentyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 4-[(3-carbamoylphenyl)methyl ]-2-pentyl-1H,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 4-[(3-cyanophenyl)methyl]-2-pentyl-1H,2H,3H, 4H-Cyclopenta[b]indole-5-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-2-ethyl-2,3,4,9-tetrahydro-1H-carbazole-8 -carboxylic acid, 9-[(3-carboxyphenyl)methyl]-2-ethyl-2,3,4,9-tetrahydro-1H-carbazole -8-carboxylic acid, 5-[(3-carbamoylphenyl)methyl]-7-ethyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 5-[(3-cyanophenyl)methyl]-7-ethyl-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid, 9-[(3-cyano Phenyl)methyl]-3-ethyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-4-propyl-2 ,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-3-propyl-2,3,4,9-tetrahydro- 1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-3-propyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 4-Butyl-9-[(3-carbamoylphenyl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 4-butyl-9-[(3- Cyanophenyl)methyl]-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 3-butyl-9-[(3-carbamoylphenyl)methyl]-2,3 ,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 3-butyl-9-[(3-cyanophenyl)methyl]-2,3,4,9-tetrahydro-1H-car Bazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl]-4-pentyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9- [(3-cyanophenyl)methyl]-4-pentyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-carbamoylphenyl)methyl] -3-pentyl-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid, 9-[(3-cyanophenyl)methyl]-3-pentyl-2,3,4, 9-tetrahydro-1H-carbazole-8-carboxylic acid, 4-[(3-carbamoylphenyl)methyl]-3-propyl-1H,2H,3H,4H-cyclopenta[b]indole-5 -carboxylic acid, 4-[(3-cyanophenyl)methyl]-3-propyl-1H,2H,3H,4H-cyclopenta[b]indole-5-carboxylic acid, 2-({7-butyl -5-[(3-carbamoylphenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indol-4-yl}formamido)acetic acid, 2-({7- Butyl-5-[(3-cia nophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indol-4-yl}formamido)acetic acid, 7-butyl-5-[(3-carbamoylphenyl) Methyl]-N-(2-hydroxyethyl)-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxamide, 7-butyl-5-[(3-cyano Phenyl)methyl]-N-(2-hydroxyethyl)-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxamide, 7-butyl-5-[(3- Fluorophenyl)methyl]-5H,6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid and 7-butyl-5-[(3-carboxyphenyl)methyl]-5H, A compound selected from the group consisting of 6H,7H,8H,9H,10H-cyclohepta[b]indole-4-carboxylic acid or a pharmaceutically acceptable salt or stereoisomer thereof. 31. A compound according to claim 30 which is a pure optical isomer. A method of inhibiting fatty acid binding protein FABP4 in a mammal, comprising:
A method of inhibiting fatty acid binding protein FABP4 in a mammal, comprising administering to the mammal an effective amount of a compound according to any one of claims 1, 17 and 23. 33. The method of claim 32, wherein the subject is a human. A compound according to any one of claims 1, 17 and 23 for use in the prevention or treatment of diseases that act on the fatty acid binding protein FABP4. 35. The method of claim 34, wherein the disease is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, atherosclerosis, intracranial atherosclerotic disease, non-alcoholic steatohepatitis, asthma, vascular dementia, multiple sclerosis, Alzheimer's disease, other chronic inflammatory diseases and autoimmune/inflammatory diseases, chronic heart disease, polycystic ovary syndrome, preeclampsia and cancer. A pharmaceutical composition comprising a compound according to any one of claims 1, 17 and 23 as an active ingredient in combination with a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition for use in the prevention or treatment of diseases that act on the fatty acid binding protein FABP4. 38. The method of claim 37, wherein the disease is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, atherosclerosis, intracranial atherosclerotic disease, nonalcoholic steatohepatitis, asthma, vascular dementia, multiple sclerosis, Alzheimer's disease, other chronic inflammatory diseases and autoimmune/inflammatory diseases, chronic heart disease, polycystic ovarian syndrome, pre-eclampsia and cancer. 39. The pharmaceutical composition according to any one of claims 36 to 38, further comprising an additional therapeutically active agent. As a method for preventing or treating a disease acting on the fatty acid binding protein FABP4,
Prevention of a disease affecting the fatty acid binding protein FABP4, comprising administering an effective amount of a compound according to any one of claims 1, 17 and 23 to a subject in need of such treatment; or method for treatment. 41. The method of claim 40, wherein the subject is a human. 42. The method of claim 40 or 41, wherein the disease is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, atherosclerosis, intracranial atherosclerotic disease, nonalcoholic steatohepatitis, asthma, vascular dementia, multiple sclerosis, Alzheimer's disease , other chronic inflammatory and autoimmune/inflammatory diseases, chronic heart disease, polycystic ovary syndrome, pre-eclampsia and cancer. As a method for inhibiting FABP4,
A method for inhibiting FABP4 comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1, 17 and 23. 44. The method of claim 43, wherein the subject is a human. Use of a compound according to any one of claims 1 , 17 and 23 for the manufacture of a medicament for use in the prevention or treatment of diseases which act on the fatty acid binding protein FABP4. 46. The method of claim 45, wherein the disease is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, atherosclerosis, intracranial atherosclerotic disease, nonalcoholic steatohepatitis, asthma, vascular dementia, multiple sclerosis, Alzheimer's disease, other chronic inflammatory diseases and autoimmune/inflammatory diseases, chronic heart disease, polycystic ovary syndrome, pre-eclampsia and cancer.